This invention relates to new solid state forms of a drug, to pharmaceutical compositions containing them, and to processes for obtaining them.
In the formulation of drug compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations comprising the active compound.
Further, in the manufacture of drug compositions, it is important that a reliable, reproducible and constant plasma concentration profile of drug is provided following administration to a patient. This is of particular importance in the manufacture of compositions comprising antithrombotic agents.
Chemical stability, solid state stability, and xe2x80x9cshelf lifexe2x80x9d of the active ingredients are also very important factors. The drug substance, and compositions containing it, should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component""s physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility).
Moreover, it is also important to be able to provide drug in a form which is as chemically pure as possible.
Amorphous materials may present significant problems in this regard. For example, such materials are typically difficult to handle and to formulate, provide for unreliable solubility, and are often found to be unstable and chemically impure.
The skilled person will appreciate that, if a drug can be readily obtained in a stable crystalline form, the above problems may be solved.
Thus, in the manufacture of commercially viable, and pharmaceutically acceptable, drug compositions, it is important, wherever possible, to provide drug in a substantially crystalline, and stable, form.
It is to be noted, however, that this goal is not always achievable. Indeed, typically, it is not possible to predict, from molecular structure alone, what the crystallisation behaviour of a compound will be. This can usually only be determined empirically.
International patent application WO 94/29336 discloses a number of compounds, which are useful as inhibitors of serine proteases, such as thrombin, including the compound,
HO2Cxe2x80x94CH2xe2x80x94(R)Cgl-(S)Aze-Pab-H
wherein Cgl represents cyclohexylglycine, Aze represents azetidine-2-carboxylate and Pab-H represents 4-aminomethylamidinobenzene. The compound is also known as melagatran (glycine, N-[(1R)-2-[(2S)-2-[[[[4-(aminoiminomethyl)phenyl] methyl] amino] carbonyl]-1-azetidinyl]-1-cyclohexyl-2-oxoethyl]-).
A process for the synthesis of this compound is described in Example 1 of WO 94/29336, where it is obtained as crude material, by evaporation of reaction solvent following a final deprotection step. The compound is thus isolated in an amorphous form.
Whether it is possible to provide melagatran in a crystalline form is not disclosed in WO 94/29336. Furthermore, no information is provided in relation to how this compound may be obtained in such a form and, more particularly, how it may be obtained in a chemically, and/or solid state, stable form.
We have found that melagatran may be readily obtained in one or more forms that are both substantially crystalline and stable in nature.
Thus, according to a first aspect of the invention there is provided melagatran in a substantially crystalline form (hereinafter referred to as xe2x80x9cthe compounds of the inventionxe2x80x9d).
Although we have found that it is possible to produce melagatran in forms which are greater than 80% crystalline, by xe2x80x9csubstantially crystallinexe2x80x9d we include greater than 20%, preferably greater than 30%, and more preferably greater than 40% crystalline. The degree (%) of crystallinity may be determined by the skilled person using X-ray powder diffraction (XRPD). Other techniques, such as solid state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) and microcalorimetry, may also be used.
The compounds of the invention may be in the form of a solvate, a hydrate or a mixed solvate/hydrate. Solvates may be of one or more organic solvents, such as lower alkyl (e.g. C14 alkyl) alcohols (e.g. methanol, ethanol or iso-propanol) or mixtures thereof.
We have found that the compounds of the invention have a surprisingly improved stability when compared with melagatran prepared as described in WO 94/29336.
According to a further aspect of the invention, there is thus provided a stable form of melagatran.
The term xe2x80x9cstabilityxe2x80x9d as defined herein includes chemical stability and solid state stability.
By xe2x80x9cchemical stabilityxe2x80x9d, we include that the compound can be stored in an isolated solid form, or in the form of a solid formulation in which it may be provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants, under normal storage conditions, with an insignificant degree of chemical degradation or decomposition.
By xe2x80x9csolid state stabilityxe2x80x9d, we include that the compound can be stored in an isolated solid form, or in the form of a solid formulation in which it may be provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants, under normal storage conditions with an insignificant degree of solid state transformation (e.g. crystallisation, recrystallisation, solid state phase transition, hydration, dehydration, solvatisation or desolvatisation).
Examples of xe2x80x9cnormal storage conditionsxe2x80x9d include temperatures of between minus 80 and plus 50xc2x0 C. (preferably between 0 and 40xc2x0 C. and more preferably ambient temperature, such as between 15 and 30xc2x0 C.), pressures of between 0.1 and 2 bars (preferably atmospheric pressure), and/or exposure to 460 lux of UV/visible light, for prolonged periods (i.e. greater than or equal to six months). Under such conditions, compounds of the invention may be found to be less than 15%, more preferably less than 10%, and especially less than 5%, chemically degraded/decomposed, or solid-state transformed, as appropriate. The skilled person will appreciate that the above-mentioned upper and lower limits for temperature and pressure represent extremes of normal storage conditions, and that certain combinations of these extremes will not be experienced during normal storage (e.g. a temperature of 50xc2x0 C. and a pressure of 0.1 bar).
The term xe2x80x9cnormal storage conditionsxe2x80x9d may also include relative humidities of between 5 and 95% (preferably 10 to 75%). However, in the case of certain crystalline forms according to the invention, changes in conformation or crystal structure by hydration and/or dehydration may occur as a result of prolonged exposure to certain extremes of relative humidities, at normal temperatures/pressures. For example, we have found that crystalline forms of melagatran that are in the form of a hydrate (e.g. a monohydrate) may be stored at 10% relative humidity or above at ambient temperature/atmospheric pressure with an insignificant degree of dehydration. However, we have also found that crystalline forms of melagatran that are in the form of an anhydrate should be stored at less than 40% (preferably less than 30%, more preferably less than 20%) relative humidity at ambient temperature/atmospheric pressure, to maintain an insignificant degree of hydration.
Thus, although compounds of the invention possess a greater solid state stability than forms of melagatran described in the prior art, some compounds of the invention are more solid state stable than others. In this respect, it will be appreciated by the skilled person that storage conditions may be tailored to suit the crystalline form that is being stored.
The compounds of the invention may be obtained advantageously by crystallising melagatran.
According to a further aspect of the invention, there is provided a process for the production of a compound of the invention which comprises crystallising melagatran.
Although metagatran may be crystallised with or without the presence of a solvent system (e.g. crystallisation may be from a melt, under supercritical conditions, or achieved by sublimation), we prefer that the crystallisation is from an appropriate solvent system.
We have found that it is possible to obtain crystalline melagatran via crystallisation advantageously following dissolution and/or suspension of the compound, or, more advantageously, from reaction solutions within which the compound has been formed.
The solvent system may include one or more organic solvents, such as alkyl acetates (e.g. linear or branched C1-6 alkyl acetates, such as ethyl acetate, iso-propyl acetate and butyl acetate), lower (e.g. linear or branched C1-6, preferably C2-4) alkyl alcohols (e.g. ethanol, iso-propanol), aliphatic and aromatic hydrocarbons (e.g. iso-octane, n-heptane and toluene), dialkyl ketones (e.g. methyl ethyl ketone and methyl iso-butyl ketone), dialkyl ethers (e.g. di-iso-propyl ether) and acetonitrile. Mixtures of any of the above-mentioned solvents may be used. Organic solvents may also be admixed with water or aqueous solutions.
Different crystalline forms may have different solubilities in different organic solvents at any given temperature. In this respect, above-mentioned solvents may be employed as xe2x80x9cantisolventsxe2x80x9d (i.e. a solvent in which compounds of the invention are poorly soluble), and may thus aid the crystallisation process. Lower alkyl alcohols are preferred solvents. When lower alkyl alcohols are employed as solvent, other solvents identified above may be employed as antisolvents (especially acetonitrile and ethyl acetate).
When the crystallisation takes place from a reaction solution in which melagatran has been formed, suitable solvents include lower alkyl alcohols (e.g. methanol, ethanol or iso-propanol) which may be in admixture with water.
Crystallisation of compounds of the invention from an appropriate solvent system may be achieved by attaining supersaturation in a solvent system which comprises melagatran (e.g. by cooling, by solvent evaporation, and/or via the addition of a suitable antisolvent). Crystallisation may also be effected by decreasing the solubility of the substance by the addition of a salt (such as NaCl).
The skilled person will appreciate that the concentration in solution of the compound that is to be crystallised, and the solvent system that is used, may influence crystallisation temperatures and crystallisation times.
The compounds of the invention may be in the form of a solvate, a hydrate or a mixed solvate/hydrate.
Compounds of the invention may also be in the form of an anhydrate. (The term xe2x80x9canhydratexe2x80x9d, when used in this context, also includes compounds that are xe2x80x9cansolvatesxe2x80x9d.) To ensure that anhydrate is produced, the solvent from which the crystallisation occurs should be dried, either before or during the crystallisation process, in order to reduce the water content below a critical level, which should preferably not be exceeded during the crystallisation. Solvent may be dried during the crystallisation process, for example by decreasing the water content of a mixture of the compound to be crystallised and an appropriate organic solvent/aqueous solvent system (e.g. by increasing the amount of organic solvent that is present and/or removal of water by formation of an azeotrope, with successive distillations). The xe2x80x9ccritical levelxe2x80x9d of water depends upon factors such as temperature, concentration in solution of the compound to be crystallised, impurity profile, and the solvent system which is employed, but may be determined non-inventively.
Thus, anhydrate may be produced by crystallisation from a solvent system, including one or more organic solvents (such as lower (e.g. C2-6) alkyl alcohols (e.g. ethanol, iso-propanol), acetonitrile and/or ethyl acetate) and/or water, which solvent system is, or is rendered during the crystallisation process, substantially free of water. By xe2x80x9csubstantially free of waterxe2x80x9d, we include that the water content in the solvent system is below that which will result in the formation of, at most, 20% monohydrate, for any particular solvent system and set of crystallisation conditions.
To ensure that monohydrate is produced, water must be present in the solvent from which the crystallisation occurs. The water content should preferably be above a critical level during the crystallisation (which xe2x80x9ccritical levelxe2x80x9d will depend upon the factors mentioned above in respect of production of anhydrate). Thus, crystalline monohydrate may be prepared by crystallising melagatran from a solvent system comprising water, and/or one or more organic solvents, including ethyl acetate, ethanol, iso-propanol, methyl iso-butyl ketone, methyl ethyl ketone, acetonitrile and mixtures thereof.
To ensure that a solvate is produced, an appropriate organic solvent, capable of forming a solvate, must be present as part of the solvent system from which the crystallisation occurs. Solvates that are in the form of xe2x80x9cmixedxe2x80x9d solvate/hydrate may also be prepared. For example, we have found that mixed lower alkyl (e.g. C1-4 alkyl) alcohol (e.g. methanol, ethanol and/or iso-propanol) solvate/hydrates may be prepared by crystallising a compound of the invention from a mixture of lower alkyl alcohols (e.g. methanol, ethanol and/or iso-propanol), water and an antisolvent (e. g. acetonitrile), for example as described hereinafter.
According to a further aspect of the invention, there is provided a compound of the invention that is in the form of a solvate, a compound of the invention that is in the form of a monohydrate, a compound of the invention that is in the form of a mixed lower (e.g. C1-4) alkyl alcoholate/hydrate (e.g. an iso-propanol solvate/hydrate), and a compound of the invention that is in the form of an anhydrate.
As may be appreciated by the skilled person, the crystalline form that is obtained depends upon both the kinetics and the thermodynamics of the crystallisation process. Under certain thermodynamic conditions (solvent system, temperature, pressure and concentration of the compound of the invention), one crystalline form may be more stable than another (or indeed any other). However, other crystalline forms that may have, in comparison, a relatively low thermodynamic stability, may be kinetically-favoured. Thus, in addition, kinetic factors, such as time, impurity profile, agitation, the presence of seeds, etc. may also influence which forms appear. Thus, the procedures discussed herein may be adapted by the skilled person as appropriate in order to obtain different crystalline forms of melagatran.
In order to ensure that crystalline forms as described herein are prepared in the absence of other crystalline forms described herein, crystallisations are preferably carried out by seeding with nuclei and/or seed crystals of the desired crystalline form in the complete absence of nuclei and/or seed crystals of other crystalline forms described herein.
Compounds of the invention that are anhydrates contain no more than 3%, preferably 1% and more preferably 0.5% (w/w) water, whether such water is bound (crystal water or otherwise) or not. Solvates, hydrates and mixed hydrates/solvates contain no less than 0.5 mol of solvent and/or water (as appropriate) per mol of melagatran.
Preferred compounds of the invention are those that are in the form of a hydrate, such as a monohydrate. According to a further aspect of the invention, there is provided a compound of the invention that contains at least 0.5, preferably 0.85 and more preferably 0.90 mol water per mol of melagatran, whether such water is bound (crystal water or otherwise) or not.
We have also found that compounds of the invention in one crystalline form can be converted into other crystalline forms. For example, crystalline monohydrate may also be formed by elutriation of other crystalline forms (e.g. anhydrates and/or other solvates) in water or a mixture of a sufficient amount of water and one or several organic solvents (such as ethanol, iso-propanol, ethyl acetate, acetonitrile or methyl iso-butyl ketone). The slurry that is formed may preferably be seeded with crystals of the crystalline monohydrate in order to ensure that an appropriate transformation takes place.
Further, drying temperature and drying time may affect the solid state properties and/or the solid state form of compounds of the invention (e.g. solvates, hydrates or mixtures thereof). For example, in the case of hydrates, dehydration may occur at low humidities and/or elevated temperatures and/or reduced pressure. For example, following the formation of crystalline monohydrate, there is a critical humidity level below which drying may be performed, which may result in crystal water being lost, and a solid state transformation to an anhydrate occurring. Conversely, anhydrates may be converted (completely or partially) to monohydrates in cases where they are subjected to an atmosphere with a relative humidity that is sufficiently high.
Thus, according to a further aspect of the invention, there is provided a process for the conversion of one crystalline form of a compound of the invention to another, which comprises recrystallising a compound of the invention from an appropriate solvent system, and/or, in the case of interconversion of anhydrate and monohydrate, subjecting the crystalline anhydrate or monohydrate (as appropriate) to an atmosphere with an appropriate relative humidity level.
The preparation, and characterisation, of inter alia anhydrate, monohydrate, and solvate/hydrate forms of compounds of the invention, are described hereinafter. Different crystalline forms of the compounds of the invention (e.g. the anhydrate and the monohydrate) may be readily characterised using X-ray powder diffraction (XRPD) methods, for example as described hereinafter.
Compounds of the invention may be isolated using techniques which are well known to those skilled in the art, for example decanting, filtering or centrifuging.
We have found that, by employing the crystallisation process as described herein, it is possible to produce compounds of the invention with a chemical purity which is above that of the melagatran which is to be isolated in the first instance.
Further purification of compounds of the invention may be effected using techniques which are well known to those skilled in the art. For example impurities may be removed by way of recrystallisation from an appropriate solvent system (e.g. lower alkyl alcohol, such as ethanol or iso-propanol), which may include antisolvent (e.g. iso-octane, acetonitrile, ethyl acetate, methyl ethyl ketone), water, or a combination of these solvents. Suitable temperatures and times for the recrystallisation depend upon the concentration in solution of the compound to be crystallised, and upon the solvent system which is used.
When compounds of the invention are crystallised, or recrystallised, as described herein, the resultant compound is in a form which has the improved chemical and solid state stability mentioned hereinbefore.
Pharmaceutical Preparations and Medical Use p In accordance with the invention, the compounds of the invention may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, or via inhalation, in the form of a pharmaceutical preparation comprising the compound of the invention in a pharmaceutically acceptable dosage form. However, we prefer that the compound of the invention is a form which is suitable for oral or parenteral, such as subcutaneous, administration.
Depending on the disorder, and the patient to be treated, as well as the route of administration, the compounds may be administered at varying doses.
According to a further aspect of the invention, there is provided a pharmaceutical formulation including a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Suitable formulations include those disclosed in international patent applications WO 94/29336, WO 96/14084, WO 96/16671, WO 97/39770, WO 97/45138, WO 98/16252 and WO 00/12043.
The compounds of the invention may be further processed before being admixed with a suitable carrier, diluent or adjuvant. For example, the crystalline form may be milled or ground into smaller particles.
We prefer that formulations comprising compounds of the invention are in a form that is suitable for parenteral (e.g. subcutaneous) delivery. In this respect, compounds of the invention can be admixed with an aqueous solvent carrier system (see, for example, international patent application WO 00/12043) in order to provide a pharmaceutical formulation that is in the form of a liquid and/or a solution.
The amount of compound of the invention which is employed in such a formulation will depend on the condition, and patient, to be treated, as well as the compound(s) which is/are employed, but can be determined non-inventively.
The compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals.
In particular, the compounds of the invention are potent inhibitors of thrombin, for example as demonstrated in the tests described in WO 94/29336. The compounds of the invention are expected to be useful in the treatment of conditions where inhibition of thrombin is required or desirable, including those described in, for example WO 94/29336 and WO 97/23499, the disclosures in which documents are hereby incorporated by reference.
Suitable doses of the compound of the invention in the therapeutic and/or prophylactic treatment of mammalian, especially human, patients are in the range 0.4 to 40 mg per day, and/or 0.0002 to 4 mg/kg (preferably 0.002 to 1 mg/kg) body weight, at parenteral administration, and 2 to 1000 mg-per day, and/or 0.001 to 100 mg/kg (preferably 0.01 to 25 mg/kg) body weight, at oral administration.
According to a further aspect of the invention there is provided a method of treatment of a condition where inhibition of thrombin is required or desired, which method includes administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment.
For the avoidance of doubt, by xe2x80x9ctreatmentxe2x80x9d we include the therapeutic treatment, as well as the prophylaxis, of a condition.
Compounds of the invention have the advantage that they are in a form which provides for improved ease of handling. Further, compounds of the invention have the advantage that they may be produced in forms which have improved chemical and solid state stability. Thus, compounds may be stable when stored over prolonged periods.
Compounds of the invention may also have the advantage that they may be prepared in good yields, in a higher purity, in less time, more conveniently, and at a lower cost, than forms of melagatran prepared previously.